Furanosyl Oxocarbenium Ion Conformational Energy Landscape Maps as a Tool to Study the Glycosylation Stereoselectivity of 2-Azidofuranoses, 2-Fluorofuranoses and Methyl Furanosyl Uronates

Article abstract of DOI:10.1002/chem.201900651

The 3D shape of glycosyl oxocarbenium ions determines their stability and reactivity and the stereochemical course of S_N1 reactions taking place on these reactive intermediates is dictated by the conformation of these species. The nature and co

Full text of DOI:10.1002/chem.201900651

A Journal of
Accepted Article
Title: Furanosyl oxocarbenium ion Conformational Energy Landscape
maps as a tool to study the glycosylation stereoselectivity of 2-
azidofuranoses, 2-fluorofuranoses and methyl furanosyl uronates
Authors: Stefan van der Vorm, Thomas Hansen, Erwin R. van Rijssel,
Rolf Dekkers, Jerre M. Madern, Herman S. Overkleeft, Dmitri
V. Filippov, Gijsbert A. van der Marel, and Jeroen D. C.
Codée
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To be cited as: Chem. Eur. J. 10.1002/chem.201900651
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Furanosyl oxocarbenium ion Conformational Energy Landscape maps as a tool to
study the glycosylation stereoselectivity of 2-azidofuranoses, 2-fluorofuranoses and
methyl furanosyl uronates
Stefan van der Vorm, Thomas Hansen, Erwin R. van Rijssel, Rolf Dekkers, Jerre M. Madern, Herman S. Overkleeft, Dmitri V. Filippov,
Gijsbert A. van der Marel and Jeroen D. C. Codée*
Abstract
The 3D shape of glycosyl oxocarbenium ions determines their stability and reactivity and the stereochemical
course of SN1-reactions taking place on these reactive intermediates is dictated by the conformation of these
species. The nature and configuration of functional groups on the carbohydrate ring effect the stability of
glycosyl oxocarbenium ions and they control the overall shape of the cations. We here map the
stereoelectronic substituent effects of the C2-azide, C2-fluoride and C4-carboxylic acid ester on the stability
and reactivity of the complete suite of diastereoisomeric furanoses using a combined computational and
experimental approach. Surprisingly all furanosyl donors studied react in a highly stereoselective manner to
provide the 1,2-cis products, except for the reactions in the xylose series. The 1,2-cis selectivity in the ribo-,
arabino- and lyxo-configured furanosides can be traced back to the lowest energy 3E or E3-conformers of the
intermediate oxocarbenium ions. The lack of selectivity of the xylosyl donors is related to the occurrence of
oxocarbenium ions, adopting other conformations.
Introduction
Stereoelectonic effects dictate the shape and behaviour of molecules. Understanding and harnessing these
effects enables the conception of effective and stereoselective synthetic chemistry.[1] Carbohydrates are
densely decorated molecules bearing a variety of different functional groups in numerous configurational
and stereochemical constellations.[2,3] The decoration pattern of carbohydrates plays an all-important role in
manipulations/transformations of the functional groups in the assembly of carbohydrate building blocks as
well as in the union of two carbohydrates in a glycosylation reaction. During a glycosylation reaction a donor
glycoside is generally activated to give an electrophilic species bearing significant oxocarbenium ion
character.[4] While steric effects are often decisive in determining the overall shape of a neutral molecule, in
charged molecules electronic effects become more important and they may in fact outweigh steric effects.
For example, protonated iminosugars, carbohydrates having the endocyclic oxygen replaced for a nitrogen,
may change their conformation to place their ring substituents in a sterically unfavourable (pseudo)-axial
orientation to stabilize the positive charge on the ring nitrogen.[5–10] In line with these stereoelectronic
effects, glycosyl donors that feature an “axial-rich” substitution pattern, are generally more reactive than
glycosyl donors equipped with equatorially disposed functional groups.[11–13] However, it is extremely
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challenging to understand - let alone predict - what the overall effect of multiple ring substituents is on the
reactivity of a particular glycosyl donor and as a result the effect on the stereoselectivity in a glycosylation
reaction. Based on a computational strategy of Rhoad and co-workers,[14] we have recently introduced a
method to determine the conformational behaviour of furanosyl oxocarbenium ions.[15–17] By calculating the
relative energy of a large number of fixed furanosyl oxocarbenium ion conformers and mapping these in
energy contour plots we could determine which conformations played an important role during
furanosylation reactions and we were able to relate the population of the different conformational states to
the stereoselectivity of the reactions. The introduced conformational energy landscape mapping method
provided detailed insight into how the ring substituents - as stand-alone entities but also collectively -
influenced the shape, stability and reactivity of the furanosyl oxocarbenium ions. In this initial study, only
ether substituents were assessed. We here present an in-depth study on the stereoelectronic substituent
effects of different functional groups that are all highly relevant in oligosaccharide synthesis. Understanding
these effects will enable the development of effective glycosylation methodologies and aid in the
interpretation of the outcome of glycosylation reactions. We have studied the effect of C2-fluoride and C2-
azide substituents, as well as C4-carboxylic acid ester groups, as these functionalities are commonly
employed in the assembly of fluorinated, cis-linked glycosamine containing or glycuronic acid featuring
oligosaccharides, respectively.[18–25]
Herein we describe the synthesis of a panel of twelve structurally varying furanosyl imidate donors,
comprising all possible pentofuranosyl diastereoisomers (Figure 1, 1-12), their glycosylation properties
studied by experimental chemical glycosylations, as well as a computational investigation on the reactive
intermediates active during the glycosylation and responsible for the stereoselective outcome of the
reaction, the furanosyl oxocarbenium ion.
Figure 1. Target donors 1-12 and the subsequent stereoselectivity investigation by glycosylations and computational analysis.
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Results and discussion
Synthesis
The set of
D
-ribo-,
D
-arabino-,
D
-lyxo- and
D
-xylo-configured furanosyl donors
1
-
12 (Figure 1) that was
needed for this study was prepared as depicted in Scheme 1. All donors studied here were equipped
with an N-phenyl trifluoroacetimidate anomeric leaving group.[26] The uronic acid methyl esters 17
-
20 were obtained from their parent methyl furanosides 13-16[27–30] by a straightforward TEMPO/BAIB
oxidation procedure of the primary alcohols, followed by methylation with MeI and K2CO3 (Scheme
1A).[31] Aqueous TFA-mediated hydrolysis of the anomeric methyl group and installation of the
trifluoro-N-phenyl imidate group with Cs2CO3 proceeded uneventfully to give donors
For the functionalization on C2 we first investigated the inversion of the C2-triflates 29
generated from the corresponding C2-alcohols 25
28[32–35] with a suitable azide or fluoride
1-4.
-32,
-
nucleophile (Scheme 1B).[36] Inversion of the ribosyl C2-OTf group in 29 using an excess of NaN3 in
DMF at 80°C proceeded smoothly to give the 2-azidoarabinoside 34 high yield (See Table 1, entry 1,
conditions A). The inversion of 29 using tetrabutylammonium fluoride (TBAF) as the source of the
fluoride nucleophile in THF at ambient temperature gave 38 in good yield (71%, Table 1, entry 2,
conditions B). This yield could be further improved to 86% by employing CsF in tert-amyl alcohol at
90°C (Table 1, entry 3, conditions C).[37]
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Scheme 1. Reagents and conditions: a) i. TEMPO, BAIB, DCM, H2O; ii. MeI, K2CO3, DMF; b) TFA/H2O (9/1); c) 2,2,2-trifluoro-N-
phenylacetimidoyl chloride, Cs2CO3, acetone, H2O; d) Tf2O, pyridine, DCM; e) NaN3, DMF, see Table 1; f) TBAF, THF; or CsF, tert-amyl
alcohol, see Table 1; g) HCOOH, H2O; h) 2,2,2-trifluoro-N-phenylacetimidoyl chloride, DBU, DCM; i) TFA, H2O, THF; j) DMAP, DiPEA,
thiophosgene, DCM; k) 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine, toluene; l) N-(phenylseleno)phthalimide, TMSN3, TBAF,
DCM; m) NIS, H2O, acetone, THF.
Table 1. Synthesis of C2-modified methyl glycosides 33-40 via C2-triflate inversion.
Substitution
product
Yield
(%)
Side products
(yield, %)
Entry Triflate
Conditionsa
from D-ribo- to D-arabino-configured
1
2
3
29
29
29
A (N3)
B (TBAF)
C (CsF)
34
38
38
93
71
86
-
-
-
from D-arabino- to D-ribo-configured
4
5
6
30
30
30
A
B
C
33
37,  only
37
86b
42
51b
30 (17)
52f (17)
63
from D-xylo- to D-lyxo-configured
7
8
32
32
32
32
32
Ac
Bd
Ce
Ac
Bd
35
39
39
35
39
67
44
-
53 (12), 55 (7)
28 (17)
9
54 (57), 55 (21)
53, (30)
54 (18), 56g
10
11
-
-
54 (47), 40
12
32
C
39
-
(10)
from D-lyxo- to D-xylo-configured
A,B,C 36 / 40
13
31
-
56g
aReagents and conditions: (A) 0.2 M solution in DMF, 5 eq. NaN3, 80°C, 2 h; (B) 0.2 M solution in THF, 2.5 eq. TBAF, 0°C to 20°C,
b
overnight; (C) 0.35 M solution in tert-amyl alcohol, 4 eq. CsF, 90°C, overnight; Combined yield of 33 and 51, as a 4:1 mixture.
g
cOvernight. d70°C, 5 h for entry 8, overnight for entry 11. e110°C overnight. f :  = 88 : 12. Yield not determined.
When the arabinoside C2 triflate 30 (a mixture of anomers) was treated with conditions A to install
the C2 azide and provide 33, a mixture of products resulted consisting of the desired C2 azide 33 and
anomeric azide 51 (Figure 2A; 86%, 33 : 51 = 4 : 1, Table 1, entry 4). Stereospecific formation of -
azide 51 (Figure 2A) can be explained by the generation of a transient methyl oxiranium ion
intermediate, that is substituted in an SN2-like fashion by the azide anion on the anomeric centre
(See Figure 2B, path A).[38]
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Figure 2. (A) Observed side products 51-56 and 40. (B) Proposed reaction pathways for the formation of 51 and 52. (C) Proposed
reaction pathways for the formation of 53, 54 (path A) and 55 (path B). (D) Proposed reaction pathways for the formation of 53,
54 (path A) and 40 (path C).
The fluoride substitution on 30 also met with side reactions. When 30 was subjected to conditions
B, using TBAF, only the
1, entry 5).[32] At higher temperatures, using CsF (Conditions C), both anomers reacted to provide the
corresponding C2-fluorides. However, reaction of the -anomer of 30 also provided the anomeric
-anomer of 30 reacted to provide 37, leaving the -anomer untouched (Table

tert-amyl product 52 (Figure 2A), resulting from a migration of the anomeric methoxide by
substitution of the C2-triflate and subsequent solvolysis of the formed oxocarbenium ion (Figure 2B,
path A, B and/or C). The weaker nucleophilicity of tert-amyl alcohol with respect to the azide anion
likely leads to more SN1-character in the substitution reaction of the methyl oxiranium ion and
generation of an anomeric mixture of 52, where the azide stereospecifically provided the
The xylosyl C2-alcohols 28 and 28 could be readily separated and their C2-triflates 32
could therefore be individually investigated in the substitution reactions (Scheme 1B, Table 1, entries
7-12). The inversion of the -anomer 32 with NaN3 provided 2-azidolyxoside 35 (67%, Table 1,
entry 7), alongside two side products, 5-azidolyxoside 53 and bicycle 55 (Figure 2A), that were

-azide 51
.



and 32





formed in 12% and 7% respectively. The generation of these side products stems from the
participation of the primary C5-OBn group, which is capable of substituting the C2-OTf. Nucleophilic
attack at C5 provides 53
Figure 2C, path A and B). When the substitution of the C2-triflate 32
to furnish the desired C-2-fluoro lyxose 39 (Table 1, entry 8), no conversion was observed and
therefore the reaction was heated to 70°C. Under these conditions 2-fluorolyxoside 39 was formed

, while substitution at the benzylic position generates and bicycle 55 (See

was tried under conditions B


in 44% yield while alcohol 28 was regenerated through hydrolysis of the triflate. Conditions C (Table
1, entry 9) only resulted in the formation of products originating from C5-OBn participation: 5-
fluoroxyloside 54

and bicycle 55 (Figure 2A and 2D) were obtained in 57% and 21% yield,
respectively.
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Inversion of the C2-OTf of the -xyloside 32 with either the azide of fluoride nucleophiles did not lead to
any desired inversion products (Table 1, entries 10-12). Conditions A only provided the C5-azido product 53
(Figure 2A), while conditions B led to the formation of 54, through the participation of the C5-OBn group
(Figure 2C, path A). Elimination to give furan 56 was also observed under conditions B (Table 1, entry 11).[39]
Interestingly, the use of CsF (conditions C, Table 1, entry 12) provided, besides sideproduct 54, the 2-
fluoroxyloside 40 in low yield, apparently through a double displacement mechanism (Figure 2D, path C).
Generation of product 40 through this route proved advantageous since its generation from lyxo-triflate 31
was ineffective (vide infra).
All the conditions examined to transform lyxo-triflate 31 to one of the inverted products (36/40)
were ineffective (Table 1, entry 13) and furan 56 was formed exclusively within minutes. We
therefore took a different approach to generate the 2-azidoxyloside (Scheme 1C). Thus, glycal 49[40]
was functionalized by azidophenylselenation with TMSN3 and N-(phenylseleno)phthalimide to give
the desired 2-azidoxyloside 50 with good diastereoselectivity (9:1, xylo:lyxo).[41,42] Oxidative
hydrolysis of the selenophenyl group by aqueous NIS then gave lactol 44
.
Acidolysis of the anomeric methyl ethers 33-35 and 37-40 using aqueous formic acid provided the other
lactols 41-43, and 45-48 (Scheme 1B). Finally, all eight lactols were transformed into the corresponding N-
phenyl trifluoracetimidates 5-12 to complete the set of donor furanosides.
Glycosylations
With the complete set of functionalized furanosyl imidate donors 1-12 in hand, the stereoselectivity
of the glycosylation reactions using allyltrimethylsilane (allyl-TMS) or triethylsilane-d (TES-d) as
acceptors, were examined.[43] Allyl-TMS and TES-d are poor nucleophiles and are ideal acceptors to
study the SN1 reaction pathways of the glycosylations at hand.[15,16,44–46] The results of these
glycosylations together with results obtained previously in the tri-O-benzyl series (donors 57-60) are
listed in Table 2. As previously described, the reactions in the tri-O-benzyl series proceed with good
to excellent 1,2-cis-selectivity for all four configurations.[15] The ribo-, arabino- and lyxo-configured
donors 57
60 gave the anomeric deuterium
13). Strikingly, the 1,2-cis-selectivity in the glycosylation reactions was also observed for the reactions
using the C2- and C5-modified furanosyl donors. All reactions performed with ribose donors and
(Table 2, entries 2-4), arabinose donors and 10 (entries 6-8), and lyxose donors and 11
(entries 10-12) proceeded with excellent 1,2-cis stereoselectivity. The reactions of the xylose donors
,
58 and 59 provided exclusively the 1,2-cis-substitution products, where the xylose donor

- and -products in a 85:15 -ratio (Table 2, entry 1, 5, 9 and

/
1, 5
9
2
,
6
3, 7
4
8
, 8, and 12 (Table 2, entries 14-16) proceed with poorer stereoselectivity. The 2-azidoxyloside donor
gives a 85:15 mixture of anomers (product 72), in line with the outcome of the reaction of the
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corresponding tri-O-benzyl donor 60 (Table 2, entry 13 and 15). The 2-fluoroxyloside 76 is formed in
a 70:30 ratio (Entry 16), and the uronic acid xyloside donor provided the least selective reaction
giving roughly equal amounts of both the - and the -product (68, Table 2, entry 14). The reactions
of the xylosyl donors also provided significant quantities of side products. In all reactions, the
anomeric N-phenyl-trifluoracetamides (78 80, Figure 3) were formed. Although these kind of side
:
4


-
products are well known for (pyranosyl) trichloroacetimidate donors,[47] to our knowledge they have
never been reported for the N-phenyl trifluoroacetimidates. In the reaction of the xyluronic acid ester
4
, the tricyclic 81 (Figure 3) was also formed, originating from an intramolecular electrophilic
aromatic substitution reaction of the C2-O-benzyl.
Overall it can be concluded that -quite surprisingly- the nature of the substituents on furanosyl donors
has relatively little effect on the stereochemical outcome of the glycosylation reactions.
Table 2. Glycosylation reactions of donors 1-12 and 57-60, with acceptors TES-d and allyl-TMS.
Yield
(%)
Entry
Donor
Acceptor
Product
1,2-cis : 1,2-trans
D-ribo-configured
1
2
3
4
57
1
TES-d
allyl-TMS
TES-d
61
65
69
73
>98 : 2
>98 : 2
>98 : 2
>98 : 2
50a
79
68
76
5
9
allyl-TMS
D-arabino-configured
62a
76
57
79
5
6
7
8
58
2
TES-d
62
>98 : 2
95 : 5
allyl-TMS
TES-d
66
6
70
>98 : 2
>98 : 2
10
allyl-TMS
74
D-lyxo-configured
100a
76
9
59
3
TES-d
63
67
>98 : 2
>98 : 2
10
allyl-TMS
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11
12
7
TES-d
71
>98 : 2
>98 : 2
59
90
11
allyl-TMS
75
D-xylo-configured
13
14
15
16
60
4
TES-d
allyl-TMS
TES-d
64
68
72
76
85 : 15
45 : 55
85 : 15
70 : 30
40a
57b
68b
62
8
12
allyl-TMS
Anomeric configuration established by HSQC-HECADE and NOESY NMR.[48–50] Detailed experimental conditions are provided
in the experimental section. aLiterature values, see reference 15. bCalculated yields from isolated mixed fractions.
Figure 3. Structures 78-81 identified as side products in the glycosylation reactions of xylosyl imidate donors. Percentages obtained
from the crude 1H NMR.
Computations
To rationalize the stereochemical outcome of the glycosylations described above, we next assessed the
structure of the oxocarbenium ions involved. Woerpel and co-workers have devised an empirical model to
rationalize the stereoselectivity observed in addition reactions to furanosyl oxocarbenium ions. This model
takes the two most relevant structures of the ions, the E3 and 3E conformers, into account and describes that
these will be preferentially attacked form the ‘inside’ of the envelope (See Figure 4A).[32,51–54] Thus, the former
ion is stereoselectively attacked from the bottom face, while the latter is substituted on the top face and the
population of both conformational states determines the overall stereoselectivity. The stereoelectronic
effects of the ring substituents dictate the relative stability of the conformers and the stabilizing/destabilizing
spatial positions are graphically presented in Figure 4B for the four tri-O-benzylfuranosyl oxocarbenium ions.
The oxocarbenium ion conformers are most stable when the positive charge at the anomeric centre is
stabilized by C2-H hyperconjugation, and by placing the alkoxy substituents at C3 and C5 in an orientation
that brings the lone pairs of the oxygen atoms closest to the anomeric centre. In the ribose oxocarbenium
ion all substituents can work in concert to stabilize the cation, while in the other three the stabilizing effect
of the substituents cannot be matched. For these ions it is difficult to predict what the net effect of the
combination of the substituents is and therefore we have developed, based on the initial work of Rhoad and
co-workers,[14] a computational method that maps the relative energy of all possible conformations as a
function of their shape. By plotting the energy of the conformers on the pseudo-rotational circle, that is used
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to graphically represent all possible 5-ring geometries (Figure 4C),[55] conformational energy landscape (CEL)
maps are created that provide detailed insight into the overall stabilizing/destabilizing effects of the ring
substituents in every possible conformation and configuration (See ESI for the full computational method).[15]
These maps can account for the stereoselectivity of addition reactions to fully or partially substituted
furanosyl oxocarbenium ions, and the method thus provides an excellent tool to assess the stereoelectronic
effects of the functional groups on the ring as a function of their electronic nature and spatial orientation.
3E
E3
Figure 4. (A) The two-conformer model, visualizing preferential nucleophilic attack from the inside face. Important rotations are
denoted by dashed arrows. (B) The two principal conformations of the two-conformer model (E3–3E) shown for every carbohydrate
configuration, examples taken as their tri-O-benzyl protected form. Colours indicate relative preferential orientations for H-2 and O-
3: green is relatively stabilizing whereas red is relatively destabilizing. (C) Pseudo-rotational circle showing the twenty canonical
furanoside structures, with phase-angle P and puckering amplitude τm. (D) The possible C4-C5 rotamers: gg, gt, and tg for the C5-
OMe oxocarbenium ions, and two rotamers, eclipsed and bisected, for the C4-CO2Me oxocarbenium ions.
We therefore adopted this method here to probe the effect of the C2- and C5-modifications on
the stability of the oxocarbenium ion conformers and we have calculated the relative energy of the
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C4-CO2Me, C2-N3 and C2-F furanosyl ions as a function of their shape to deliver the CEL maps shown
in Figure 5. To generate these maps the benzyl ethers in the substrates used in the experiments
described above have been replaced for methyl ethers (See Figure 5, 82-97), to minimize
computational costs.[56] For the C2-N3 and C2-F ions, three maps were generated for each of the C4-
C5 gg, gt, and tg rotamers (Figure 4D), and these were combined to provide the overall CEL map
shown in Figure 5. A similar approach was taken for the bisected and eclipsed structures of the C4-
CO2Me oxocarbenium ions. The most important conformations for each ion are given next to the CEL
map of each oxocarbenium ion in Figure 5 (see ESI for the corresponding energies).
From the CEL maps of the ribo-configured furanosyl oxocarbenium ions 82-85 (Figure 5, top row)
it becomes clear that the overall shape of the energy landscape is comparable for all four ions, with
the energy minima centred on the E3 conformation. This indicates that a fluoride or azide at C2 is
best positioned in a pseudo-equatorial orientation to allow for stabilization of the ion by
hyperconjugation of the C2-H bond, in line with the effect of a C2-ether functionality.[8,15] From the
CEL map of the C2-F ion it does become apparent that there is a stronger tendency of the fluorine
3
atom to occupy a pseudo-equatorial orientation. The E conformer of 85 is 5.2 kcal∙mol-1 higher in
energy than the lowest energy E3 conformer, whereas this difference is only 1.9 kcal∙mol-1 for 82 and
around 2.5 kcal∙mol-1 for 84. The preference of the C4-CO2Me to take up an axial orientation becomes
apparent from the CEL map of ion 83. Interestingly, there is only a marginal difference between the
eclipsed and bisected orientation of the carboxylic acid ester and both orientations seem to be
equally capable of stabilizing the electron depleted anomeric centre when the C4-CO2Me takes up a
pseudo-axial orientation (See ESI). Using the lowest energy E3 conformers as product forming
intermediates the formation of the 1,2-cis products can be readily accounted for using the inside
attack model for all of the examined ribofuranosides.
The CEL maps for arabino-configured furanosyl oxocarbenium ions 86-89 (Figure 5, second row)
3
also show great similarity, with each map showing an energy minimum around the E conformation.
Thus, the hyperconjugative stabilization of the C2-H bond, in combination with a sterically favourable
pseudo-equatorial orientation for all substituents seems decisive for these ions. Inside attack on the
3E conformers leads to the formation of the 1,2-cis-products as found experimentally. Of note, the
4
4
C2-N3 CEL map does show a second energy minimum for the T3 / E conformer with minimal ring
puckering. From the stereochemical outcome of the glycosylation reactions it seems that this
conformer does not play a major role in the addition reaction. This could indicate that attack on this
almost flat conformer is significantly less favourable than the inside attack of the 3E envelope, which
leads to the favourable C1-C2 staggered product.
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82 (D-ribose)
83 (4-CO2Me-D-ribose)
84 (2-N3-D-ribose)
85 (2-F-D-ribose)
86 (D-arabinose)
87 (4-CO2Me-D-arabinose)
88 (2-N3-D-arabinose)
89 (2-F-D-arabinose)
90 (D-lyxose)
91 (4-CO2Me-D-lyxose)
92 (2-N3-D-lyxose)
93 (2-F-D-lyxose)
94 (D-xylose)
95 (4-CO2Me-D-xylose)
96 (2-N3-D-xylose)
97 (2-F-D-xylose)
Figure 5. Conformational Energy Landscape maps for the four diastereoisomeric pentofuranosides and their C5- and C2-modifications
푇
respectively. Energies expressed as ∆퐺퐷퐶푀 in kcal∙mol-1.
The CEL maps of the lyxo-configured oxocarbenium ions 90-93 (Figure 5, third row) show a single energy
minimum on the 3E-side of the CEL map and the difference in energy between these structures and the other
conformers appears to be even larger than the energy differences observed for the ribosyl oxocarbenium
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10.1002/chem.201900651
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ions. This can be understood by realizing that the E3 envelope not only loses the stabilizing interactions of
the C2 and C3 substituents, present in the 3E conformer, but also experiences severe 1,3-diaxial interactions
between the C2 and C4 groups, especially for the electronically most favorable gg rotamer. Again, the CEL
maps show great similarity for all substitution patterns, indicating analogous behaviour of the
lyxofuranosides in glycosylation reaction. This is indeed borne out in the experimental glycosylations that all
proceed in an completely stereoselective fashion, to provide the all-cis products.
Finally, the xylo-configured oxocarbenium ions 94-97 (Figure 5, fourth row) were assessed. Again, the CEL
maps of the differently functionalized xylosides appear to be rather similar. Two minima are apparent on
either side of the CEL maps. In the low energy E3-like structures the C5-OMe groups are positioned in a gg
orientation to stabilize the electron depleted anomeric centre, while in the low energy 3E-like structures, on
the other side of the CEL map, the C5-OMe takes up a gt orientation. Notably, the energy minima located on
the south side of the CEL maps are relatively broad and not only encompass E3-like conformations but also
4T3 structures, and perhaps more striking, the 4E-like conformers. This latter conformer is in fact the lowest
energy species for 2-fluoroxyloside 97 and xylosyl uronate 95, which are the two least selective species (see
Table 2). This conformation lacks the stabilizing effect of the O3 electron lone pairs as well as
hyperconjugative stabilization by the C2-H bond. Instead, the driving stabilization now appears to be the
interaction of the C5-O-methyl or C5 carbonyl that is positioned over the ring in an eclipsed conformation,
with the anomeric centre. In the 4E conformation, the steric interactions between C5 and the substituents at
C3 and the C2-H are reduced when compared to the sterically unfavourable situation in the E3 conformer.
The established broad energy minima may be at the basis for the poor stereoselectivity observed in the
condensations of the xylosyl donors as attack of the 4E conformers may occur from both sides of the ring.
Conclusions
In summary, we have disclosed synthetic routes to access all diastereoisomeric C2-azido and C2-fluoro
furanosides as well as all furanosyl uronic acid esters. In total a set of twelve differently functionalized
furanosyl donors has been synthesized and these have been glycosylated with allyltrimethylsilane and
triethylsilane-d to establish the stereoselectivity of these donors in SN1-type glycosylation reactions. Exclusive
1,2-cis-selectivity was observed for all ribo-, arabino-, and lyxo-configured donors, despite the structural
modifications made on the C2- and C5-positions. The 2-azido and 2-fluoro xylose donors were moderately
1,2-cis-selective while the xyluronic acid donor reacted in a non-stereoselective manner. The experimental
results have been complemented by computational studies, generating Conformational Energy Landscape
(CEL) maps for the intermediate oxocarbenium ions. These maps have shown that the stereoelectronic
effects of the C2- and C5-modifications are, across the board, similar to an C2-ether substituent. These groups
therefore have a similar effect on the stereochemical outcome of glycosylations reactions taking place
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through an SN1-like mechanism and the lowest energy oxocarbenium ion conformers, revealed by the CEL
maps have, in combination with the inside attack model, provide a suitable explanation for the
experimentally observed cis-stereoselectivity. The maps have revealed that for most of the studied furanosyl
oxocarbenium ions the canonical 3E and E3 envelopes represent the lowest energy structures. However, for
the xylosyl oxocarbenium ions other low energy structures can be found, taking up 4T3 and 4E conformations.
The occurrence of these structures coincides with relatively poor selectivity in the addition reactions. For
these ions it appears that the “two-conformer model” falls short in providing an adequate explanation to
account for the (lack of) stereoselectivity and that more oxocarbenium ion conformations have to be taken
into account as product forming intermediates. Further insight into the structure of glycosyl oxocarbenium
ions and the trajectories of nucleophiles that attack these will lead to a better understanding of the SN1-side
of the glycosylation reaction mechanism continuum and this can eventually pave the way to new
stereoselective glycosylation methodology.[57]
Acknowledgements
We thank the Netherlands Organization for Scientific Research (NWO) for financial support and the use of
supercomputer facilities (SURFsara and the Lisa system) and we kindly acknowledge Mark Somers for
technical support.
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Table of Contents Graphic
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